Dizziness and imbalance problems affect more than 90 million Americans and are one of the most common complaints in clinic patients. These symptoms can be caused by a range of vestibular and neurological disorders, but almost two-thirds of dizziness cases are a result of Meniere's disease, migraine-associated vertigo (MAV), and phobic postural vertigo/chronic subjective dizziness (PPV/CSD). The etiology of all these disorders is still unclear and successful pharmaceutical treatments are lacking.
Meniere's Disease
In 1861 Prosper Meniere first published an article describing an inner ear disorder that caused vertigo and hearing loss.i Today the disorder, known as Meniere's disease (MD) affects 20 to 200 per 100,000 individuals with men and women (typically between 30-50 years old) being affected almost equally.ii Meniere's disease continues to be characterized by the same symptoms described in 1861. The American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS) criteria for diagnosis includes recurrent spontaneous and episodic vertigo (vertigo that is debilitating and usually causes nausea or vomiting without loss of consciousness) that lasts at least 20 minutes and up to several days with hearing loss, aural fullness and/or tinnitus.iii This vestibular disorder has several proposed causes, but is truly idiopathic due to inconsistent symptoms without explanations. It is commonly thought that endolymphatic hydrops causes Meniere's disease.iv Hydrops form either because a blockage prevents the endolymphatic fluid from being properly absorbed or because there is an excess in endolymphatic fluid production. The resulting increase in inner ear pressure is proposed to then cause vertigo attacks and the aural fullness sensation characteristic of Meniere's disease.v However, hydrops may be an epiphenomenon rather than the primary cause because it is not found in every Meniere's patient. Additionally, one study has discovered that animal models do not present differences in hydrostatic pressures in the perilymph and endolymph despite the presence of significant hydrops.vi Other underlying causes of Meniere's disease have been researched, like spreading depression and characteristically similar migraines.
Migraine has been frequently associated with Meniere's disease and the two disorders share several likenesses. A study on the comorbidity of migraine and Meniere's disease found a significantly higher lifetime prevalence of migraine in the MD group compared to an age- and sex-matched control group: 44 out of 78 patients with MD (56%) had a history of migraine compared to 20 out of 78 in the control group (25%) for both men and women.vii The same study found that 35 (45%) patients reported Meniere's attacks were always accompanied by at least one migrainous symptom (migrainous headaches, photophobia, or aural symptoms) and 9 (11%) patients reported Meniere attacks were sometimes accompanied by migrainous symptoms. In our own research on dizziness and balance disorders between 2011 and 2012 we found that 90 patients were diagnosed with Meniere's disease and of these patients 13 (14%) individuals were diagnosed with migraine and 10 (11%) individuals were diagnosed with anxiety and migraine, composing a total of 23 (25%) patients who were diagnosed with some form of migraine. Both vestibular disorders have a similar non-drug treatment as well, including avoidance of caffeine, chocolate, alcohol, tobacco and salt.viii Additionally, Meniere's disease and migraines both have significant genetic components and it is possible that patients are inheriting ion channel abnormalities shared by the brain and inner ear that causes both disorders.ix It has not been definitively determined whether migraine mimics Meniere's disease or causes it, but the several commonalities suggest that MD patients with migraine may find relief with antimigrainous medication.
Anxiety is another diagnosis frequently seen with Meniere's disease (MD). Many MD patients become anxious, depressed or stressed due to the severe repeated vertigo. This anxiety can even develop into a secondary vestibular disorder: phobic postural vertigo (or chronic subjective dizziness if symptoms persist for more than 3 months). A study assessed MD patients using the Dutch Daily Hassles List, Coping Inventory for Stressful Situations (CISS), Symptoms Checklist 90 (SCL-90), NEO Five Factor Inventory (NEO-FFI), General Health Questionnaire (GHQ-12), and the Short Form Health Survey 36 (SF-36).x The results showed that Meniere's disease patients did not have any abnormalities in personality, but had more daily stressors, had a worse quality of life and more instances of anxiety and depression compared to a healthy control group. These psychological difficulties were more profound in patients who had been living with Meniere's disease for a longer time and in those who experienced more frequent symptoms. Another study found that more than half of the 800 Meniere's patients enrolled reported experiencing partial or full posttraumatic stress disorder symptoms.xi Our own preliminary analysis revealed a similar pattern of anxiety comorbidities with, again 10 (11%) of 90 MD patients diagnosed with both anxiety and migraine and 26 (29%) patients diagnosed with only anxiety. These numbers combined with migraine prevalence totaled to slightly more than half (54%) of our total MD sample with an anxiety and/or migraine comorbidity. However, most treatments for Meniere's disease do not address migraine or anxiety symptoms.
In addition to the aforementioned lifestyle and diet changes, Meniere's disease can be treated in a variety of ways, all of which are short of being complete successes for one reason or another. Streptomycin therapy, while effective in vertigo control, after repeated treatments has an ototoxic effect and must be stopped if the patient experiences a rapid decline in vestibular function, develops hearing loss or manifests oscillopsia.xii Intratympanic gentamicin also has a high rate of sensorineural hearing loss.xiii The efficacy of invasive surgery is questionable as well. A study conducting both endolymphatic sac surgeries and mastoidectomies indicated that the benefits of endolymphatic sac surgery may be a surgical placebo effect.xiv Patients who undergo vestibular neurectomies rarely have a reoccurrence of vertigo and have no risk of hearing loss. Despite these positive results, the procedure is very stressful and older patients are ineligible because of the greater difficulty to compensate for lost vestibular function. Irrefutably the treatment with the least side effects is the Meniett device, but many patients cannot afford the device priced around $3,500 because of reluctant insurers. A lot of pharmacotherapy research has been conducted too; however, few have advanced to clinical usage. Most studies, such as those on the effects of betahistine, do not meet high methodological standards and the evidence is deemed inconclusive.xv Most importantly, the majority of these treatments are merely symptomatic and an effective prophylactic intervention has not yet been developed.
Migraine-Associated Vertigo (MAV)
Beyond the many commonalities shared between migraines and Meniere's disease, migraines also have their own frequent comorbidity with vertigo and dizziness. In a study conducted by Kayan and Hood, motion sickness was reported by over half of the participants diagnosed with migraine.xvi Another study revealed 3.2% comorbidity between migraine and vertigo in the general population despite an expected overlap of only 1.1% by chance alone.xvii Researchers reasoned that this increased prevalence could be due to a higher occurrence of dizziness and vertigo symptoms in migraine patients than in controls, but also could be caused by the recent recognition of migraine-associated vertigo (MAV) as its own vestibular disorder. The details of migraine-associated vertigo regarding terminology, causation, criteria, and treatment are still highly debated. However, Neuhauser et al.'s criteria have been commonly used to diagnosis patients.xviii Definite migraine-associated vertigo is based on the patient having episodic vestibular symptoms of at least moderate severity (rotational vertigo, other illusory self or object motion, positional vertigo or head motion intolerance), migraine according to the International Headache Society (IHS) criteria, at least one migrainous symptom during at least two vertiginous attacks (migrainous headache, photophobia, phonophobia, or visual or other auras), and all other causes ruled out by appropriate investigations. A probable diagnosis of migraine-associated vertigo is based on episodic vestibular symptoms of at least moderate severity; at least one migraine according to the IHS criteria, migrainous symptoms during vertigo, migraine-specific precipitants of vertigo (specific foods, sleep irregularities, hormonal changes), or response to anti-migraine drugs; and all other causes ruled out by appropriate investigations. There are more women than men with symptoms of migraine; in the United States rates range from 16-18% for women and 5-6% for men.xix Although general population prevalence rates have not been calculated, if sample study statistics are reflective of the population it would be expected that 4.5% of women and 1.5% of men in the U.S. experience migraine associated vertigo. Yet, because the exact mechanisms of this disorder are still debated, effective prophylactic treatment that could greatly improve the quality of life for these individuals has not been implemented.
Most MAV patients are given medications that will only abort symptomatic vertigo and migraine attacks once they are already occurring. These medications include benzodiazepines (Valium), cyproheptadine, ergots, methysergide, non-steroidal anti-inflammatory drugs (Ibuprofen), opiates or triptans (Maxalt, Relpax).xx Nonpharmacologic remedies include butterbur root extract, dietary restrictions (caffeine), food supplements, magnesium, and better sleep hygiene. Common prophylactic treatments for migraine such as beta-blockers, calcium antagonists, anticonvulsants (topiramate or depakote) and antidepressants are frequently being used in MAV cases, although it is still debated whether these medications have a positive effect on both migraine and vertigo aspects of MAV. All of these treatment options lack a high-level of evidence and randomized controlled study designs. Further complicating efficient treatment for MAV patients is anxiety comorbidity and anxiety-related dizziness (PPV). It is well recognized that migraine commonly occurs with symptoms of depression and anxiety. For instance, the life time prevalence of panic disorder is 16% in patients with migraine compared with 4% in control groups.xxi Eckhardt-Henn et al. concluded that migraine-associated vertigo and Meniere's disease seem to be the vestibular disorders with the highest risk of secondary anxiety symptoms.xxii An approach that embraces both prophylactic MAV treatment and anti-anxiety medication will provide patients with the most relief, but such an approach has not previously been available. The present invention meets these and other needs related to prophylaxis and therapy of dizziness with several distinct etiologies.